Long-term clearance of hepatitis C virus following interferon α-2b or peginterferon α-2b, alone or in combination with ribavirin.

Sustained virologic response (SVR) is the standard measure for evaluating response to therapy in patients with chronic hepatitis C (CHC). The aim of this study was to prospectively assess the durability of SVR in the pivotal studies of peginterferon (PEG-IFN) α-2b or IFN α-2b. We conducted two phase 3b long-term follow-up studies of patients previously treated for CHC in eight prospective randomized studies of IFN α-2b and/or PEG-IFN α-2b. Patients who achieved SVR [undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of treatment] were eligible for inclusion in these follow-up studies. In total, 636 patients with SVR following treatment with IFN α-2b and 366 with SVR following treatment with PEG-IFN α-2b were enrolled. Definite relapse (quantifiable serum HCV RNA with no subsequent undetectable HCV RNA) was reported in six patients treated with IFN α-2b and three patients treated with PEG-IFN α-2b. Based on these relapses, the point estimate for the likelihood of maintaining response after 5 years was 99.2% [95% confidence interval (CI), 98.1-99.7%] for IFN α-2b and 99.4% (95% CI, 97.7-99.9%) for PEG-IFN α-2b. Successful treatment of hepatitis C with PEG-IFN α-2b or IFN α-2b leads to clinical cure of hepatitis C in the vast majority of cases.

All-oral direct-acting antiviral therapy in HCV-advanced liver disease is effective in real-world practice: observations through HCV-TARGET database.

BACKGROUND: Chronic hepatitis C virus therapy in patients with advanced liver disease remains a clinical challenge. HCV-TARGET collects data in patients treated at tertiary academic and community centres. AIM: To assess efficacy of all-oral HCV therapy in advanced liver disease. METHODS: Between December 2013 and October 2014, 240 patients with a MELD score of ≥10 initiated HCV treatment with an all-oral regimen. Data from the 220 patients who completed 12-week follow-up were analysed. RESULTS: Genotype 1 (GT1) patients had higher sustained virological response (SVR) when treated with sofosbuvir plus simeprevir ± ribavirin than with sofosbuvir plus ribavirin (66-74% vs. 54%); GT1b vs GT1a (84% vs. 64%). SVR for GT2 was 72% with sofosbuvir plus ribavirin, while GT3 patients had a substantially lower response (35%). A decrease in MELD score was not clearly related to SVR over the short course of follow-up although some had improvements in MELD score, serum bilirubin and albumin. A predictor of virological response was albumin level while negative predictors were elevated bilirubin level and GT1a. Most patients with GT1 were treated with approximately 12-week duration of sofosbuvir and simeprevir ± ribavirin therapy while GT2 and GT3 patients were treated with approximately 12 and 24 weeks of sofosbuvir plus ribavirin respectively. CONCLUSIONS: All-oral therapies are effective among patients with advanced liver disease with high levels of success in GT2 and GT1b, and may serve to reduce the severity of liver disease after SVR. Treatment for GT3 patients remains an unmet need. Clinical trial number: NCT01474811.

Hepatic decompensation in patients with cirrhosis during infection with influenza A.

BACKGROUND: Patients with chronic liver disease can develop hepatic decompensation during systemic infections. Although gram-negative and gram-positive bacteria are well recognized as causes of decompensation, the effect of influenza virus infection on patients with chronic liver disease is poorly documented. METHODS: Retrospective analysis of patients with positive viral cultures who were seen at a liver transplantation clinic in a tertiary care referral center during the 1997-1998 influenza A (H3N2) epidemic in San Diego, Calif. RESULTS: Three patients with end-stage liver disease (1 with Wilson disease and 2 with alcoholic liver disease) developed hepatic decompensation and required hospitalization during infection with influenza A. Two patients had biochemical and clinical evidence of hepatic decompensation, including ascites, hepatic encephalopathy, and peripheral edema, and the third had acute hepatocellular damage, with elevated levels of aminotransferases. Viral hepatitis serologic test results, acetaminophen levels, drug and alcohol screening findings, and bacterial and fungal cultures were negative in all 3 patients. Hepatic decompensation resolved without the need for transplantation in the 2 patients with liver failure, and all patients recovered to their baseline liver function levels within 1 month of onset of acute illness. CONCLUSIONS: Influenza A infection can cause hepatic decompensation and hospitalization in patients having cirrhosis or who are awaiting liver transplantation. Effective prevention with vaccination and early recognition and treatment of influenza are strongly recommended in these individuals.

Mastocytosis: diverse presentations and outcomes.

Within the general category of mastocytosis lies an array of clinical presentations with differing prognostic implications. We report 3 cases of systemic mastocytosis distinguished by novel aspects of the disease. Case 1 documents the first successful orthotopic liver transplantation in a patient with mastocytosis; case 2 depicts a potential hereditary component of mastocytosis; and case 3 documents the progression of mastocytosis with hematologic abnormality to mast cell leukemia. Future investigations, such as the early definition of c-kit receptor mutations, may provide additional insight as to the molecular basis for this heterogeneous disease and guidance for prognostic implications and targeted therapies.

An urgency to identify and treat chronic hepatitis C.

The human and monetary costs of chronic hepatitis C and the complications arising from this disease, including hepatocellular carcinoma and liver transplantation, emphasize the increased urgency to treat hepatitis C virus (HCV)-infected patients earlier in the course of their disease. The current standard of treatment for patients chronically infected with HCV is combination therapy with pegylated interferon plus ribavirin. Among undertreated groups of patients are those with persistently normal alanine aminotransferase levels, those coinfected with human immunodeficiency virus and HCV, and nonresponders to previous treatment with standard interferon. This review summarizes the rationale for earlier treatment of chronic HCV infection, as well as evidence showing that patients who do not achieve a virologic response on treatment may derive benefit from treatment, including improved histologic characteristics and delayed progression of disease.

Idiopathic fatty liver of pregnancy: findings in ten cases.

Ten cases of fatty liver of pregnancy are reported from a large metropolitan medical center for the period 1972 to 1982. Compared to earlier reports, a marked decrease in both maternal and fetal mortality was noted (1 mother died and 2 of 12 infants were stillborn). Eight other cases obtained from liver biopsies referred from other hospitals were also reviewed and combined mortality data were similar. Since delivery was spontaneous in 8 of our 10 patients, the lower mortality cannot be attributed to early delivery. Instead, we ascribe it to improved supportive therapy with transfusions, clotting factors, antibiotics, glucose and monitoring. Also, earlier reports emphasized autopsy material. The incidence of FLP was 1 per 13,328 deliveries in a predominantly Hispanic population. Our review yielded new data concerning presenting signs and symptoms, laboratory features including serial clotting screens documenting disseminated intravascular coagulation (DIC), obstetric and perinatal information as well as maternal follow-up.

The management of side-effects during therapy for hepatitis C.

The results of interferon and ribavirin combination therapy for chronic hepatitis C infection have substantially improved in recent years, such that the majority of patients in randomized-controlled trials now achieve a sustained virological response. However, adverse effects are commonplace, often disabling and may lead to interruption or cessation of therapy with subsequent loss of efficacy. Constitutional, neuropsychiatric and haematological reactions have proved particularly troublesome. In this review, we discuss these adverse effects in more detail and highlight recent advances in their management.

Heparin-induced thrombocytopenia and thrombosis: detection and specificity of a platelet-aggregating IgG.

A 46-year-old female who died as a result of thrombocytopenia associated with multiple arterial occlusions and septicemia while on heparin therapy was found to have a platelet-aggregating factor present in several plasma samples and in a sample of serum. This factor was subsequently shown to be an IgG with aggregating properties toward normal platelets that were enhanced by, but not dependent on, the presence of heparin. Further studies showed that heparin was unlikely to have acted as a hapten in initiating the IgG production but that its role was significant in aggravating the ensuing arterial thrombosis. The necessity of substitution of heparin with alternative anticoagulant/antithrombotic therapy to avoid the worst sequelae of this potentially catastrophic syndrome is discussed.

Novel therapeutic approaches for hepatitis C.

Chronic hepatitis C virus (HCV) infection afflicts a reported 170 million people worldwide and is often complicated by cirrhosis and hepatocellular carcinoma. Morbidity and mortality are decreased with the successful treatment of chronic HCV infection. The current standard of care in the treatment for genotype 1 chronic HCV is pegylated interferon (IFN)-alfa, termed PEG, and ribavirin (RBV) in conjunction with a protease inhibitor, either telaprevir or boceprevir, which results in 67-75% sustained viral response rates. Increased understanding of the HCV has allowed further development of new direct-acting antiviral (DAA) agents against the HCV and has also allowed the development of IFN-free oral treatment regimens. We anticipate the approval in late 2013 of the first nucleotide polymerase inhibitor regimen with RBV alone for genotypes 2/3 and in combination with a 12-week regimen of PEG+RBV for genotypes 1, 4, 5, and 6. Most of the promising new DAA regimens are discussed herein.

Hepatitis C virus therapy is associated with lower health care costs not only in noncirrhotic patients but also in patients with end-stage liver disease.

BACKGROUND: The effect of anti-viral treatment on downstream costs for hepatitis C virus (HCV)-infected patients is unknown. AIM: To evaluate follow-up costs in patients with chronic HCV, stratified by liver disease severity. METHODS: Using a US private insurance database, mean all-cause per-patient-per-month (PPPM) US (2010) medical costs were calculated for HCV-infected persons who did and did not receive anti-HCV treatment between January 2002 and August 2010. Analysis was stratified by liver disease severity [noncirrhotic disease (NCD), compensated cirrhosis (CC) or end-stage liver disease (ESLD)] defined by ICD-9 and CPT codes. RESULTS: A total of 33 309 patients were included (78% NCD, 7% CC and 15% ESLD); 4111 individuals (12%) received anti-HCV treatment during the 2-year baseline period. Mean PPPM follow-up health care costs were significantly lower among treated patients with NCD ($900 vs. $1378 in untreated patients, P < 0.001) and ESLD ($3634 vs. $5071, P < 0.001) groups but not in the CC group ($1404 vs. $1795, P < 0.071; t-test). In a multivariable model adjusted for demographic characteristics, comorbidities, index date and geographical region, incremental cost ratios for total health care costs differed significantly (P < 0.001) between treated and untreated patients in the NCD and ESLD groups but not in the CC group. From this model, mean PPPM total health care costs between treated and untreated patients were $885 and $1370 in the NCD, $1369 and $1802 in the CC, and $3547 and $5137 in the ESLD groups, respectively. CONCLUSIONS: Anti-HCV therapy was associated with lower follow-up US health care costs, and these savings were independent of baseline patient comorbidities and stage of disease.

Histological benefits of virological response to peginterferon alfa-2a monotherapy in patients with hepatitis C and advanced fibrosis or compensated cirrhosis.

BACKGROUND: Patients with chronic hepatitis C virus and advanced fibrosis or cirrhosis are at risk for disease progression and hepatic decompensation. AIM: To determine the effects on hepatic histology of treatment with peginterferon alfa-2a (90 or 180 mug/week) or interferon alfa-2a (3 million units three times weekly) for 48 weeks in patients with paired biopsies. METHODS: Liver biopsies were obtained at baseline and 6 months after end of treatment. Histological and virological responses were compared. RESULTS: Patients attaining sustained virological response (n = 40) demonstrated the greatest improvements in fibrosis (-1.0, P < 0.0001) and inflammation (-0.65, P < 0.0001). Patients who cleared hepatitis C virus during treatment, but later relapsed (n = 59), experienced less improvement in fibrosis (-0.04, P < 0.0001) and inflammation (-0.14, P = 0.0768). Nonresponders (n = 85) showed no significant improvement in inflammation or fibrosis. Multiple regression analysis showed that the only factors contributing to improvement in fibrosis were sustained virological response (vs. nonresponder, P = 0.0005; vs. relapse, P = 0.7525) and body mass index < or =30 kg/m2 (P = 0.0995). CONCLUSIONS: These findings indicate that virological response to peginterferon alfa-2a improves inflammation and fibrosis in hepatitis C virus patients with advanced fibrosis or cirrhosis. Improving virological response and maintaining ideal body weight are critical for achieving optimal histological outcomes in hepatitis C virus patients.

Golytely lavage versus a standard colonoscopy preparation. Effect on normal colonic mucosal histology.

We prospectively studied the changes of colonic mucosa in patients receiving two different preparations for colonoscopic examination. Eighteen consecutive patients undergoing colonoscopy for polyps or mass lesions, properly age- and sex-matched, were randomized to receive Golytely lavage (3-4 L) or a standard preparation (48-h clear liquid diet, 240 ml of magnesium citrate and "X-Prep" senna derivative). Patients with diarrhea or inflammatory bowel disease, or both, were excluded. Biopsy specimens were obtained from normal-appearing mucosa of the right and left side of the colon (none in the distal 10 cm of rectum). Blind review of coded slides was performed with 0-3 scoring for artifact, edema and hemorrhage of the lamina propria, surface epithelial and goblet cells, crypts, and cells in the lamina propria including eosinophils and polymorphonuclear leukocytes. Statistically significant differences were found for preservation of surface epithelial and goblet cells and less edema in favor of patients receiving Golytely. We conclude that the standard form of colon preparation flattens the surface epithelial cells and depletes the goblet cells as well as causes an increase in lamina propria edema, whereas colon lavage preserves normal mucosal histology.

Rapid diuresis in patients with ascites from chronic liver disease: the importance of peripheral edema.

Serial measurements of plasma volume and ascites volume were made during treatment with large doses of oral diuretics in 14 patients with stable chronic liver disease. Eight patients had pitting edema in addition to ascites. Reproducibility of ascites and plasma volume measurements was verified in 10 control subjects not receiving diuretics. Six patients without edema undergoing rapid diuresis lost a mean of 1.2 +/- 0.2 L of ascites and an equivalent amount of weight (1.3 +/- 0.4 kg) per day. All had a rise in blood urea nitrogen or creatinine, or both, and a fall in creatinine clearance. Eight patients with edema undergoing rapid diuresis lost more weight (1.8 +/- 0.5 kg/day, p = 0.06) but less ascites (0.7 +/- 0.35 L/day, p less than 0.05) than those without edema, and none developed renal insufficiency. After edema disappeared, ascites mobilization increased (1.4 +/- 0.7 L/day) and renal dysfunction occurred. Plasma volume fell an average of 24% +/- 9% in patients without edema but did not change in patients with edema (-0.4% +/- 3%). When edema disappeared, plasma volume fell significantly (28% +/- 8%, p less than 0.001). Electrolyte changes including hyponatremia, hyperkalemia, and hypochloremia were seen only in the group without edema. Patients with ascites and no edema are able to mobilize more than 1 L/day during rapid diuresis, but at the expense of plasma volume contraction and renal insufficiency. Patients with peripheral edema appear to be protected from these effects because of the preferential mobilization of edema and may safely undergo diuresis at a rapid rate (greater than 2 kg/day) until edema disappears.

Pulmonary infarction after liver transplant and previous hepatopulmonary syndrome.

We describe the case of a 36-year-old woman with previous hepatopulmonary syndrome in which a focal pulmonary lesion developed after liver transplantation. Thoracoscopic resection showed a pulmonary infarction of the superior segment of the right lower lobe. The patient recovered and had no further thrombotic events after 2 years of follow-up. The pulmonary vascular changes observed during hepatopulmonary syndrome may predispose patients to the development of pulmonary infarction.

LKM-positive autoimmune hepatitis in the western United States: a case series.

OBJECTIVE: LKM-positive, or type 2, autoimmune hepatitis is characterized by the presence of antibodies directed against liver-kidney microsomes (LKM1). Although described frequently in southern Europe and the Mediterranean, this subtype of autoimmune liver disease seems to be extremely rare in northern Europe and in the United States. We report here five cases of LKM-positive autoimmune hepatitis that were seen at our center in the period 1989-1999. METHODS: We reviewed the medical records of all patients with the diagnosis of AIH in our institution during the period 1989-1999, and found that five patients had type 2 AIH. All patients were female; four of five were young, and four of five presented with overt cirrhosis. RESULTS: One patient died, one underwent liver transplantation and two are currently awaiting liver transplantation. Response to conventional immunosuppressive therapy was poor and two patients required treatment with cyclosporine and tacrolimus respectively. Four of five patients had at least one associated autoimmune disorder, including IgE-induced IgA deficiency, idiopathic thrombocytopenic purpura (ITP), and arthritis. HLA class II DR4 was present in two patients. CONCLUSIONS: LKM-positive autoimmune hepatitis seems to be a subset of autoimmune hepatitis with distinct clinical features; although rare, it is occasionally encountered in the western United States. Prompt diagnosis and appropriate immunosuppressive treatment are recommended, as well as early referral to transplantation centers. Clinicians should be aware of this condition in the setting of young female patients with unexplained severe liver disease.

Influenza infection in patients before and after liver transplantation.

Infection with influenza virus poses specific problems in pediatric and adult liver transplant recipients, both before and after liver transplantation. These include a higher rate of pulmonary and extrapulmonary complications, development of rejection with graft dysfunction, prolonged shedding of influenza virus, and increased drug-resistance. Hepatic decompensation may occur during influenza infection in patients with cirrhosis. Current prophylaxis includes yearly vaccination with trivalent inactivated vaccine. Appropriate diagnosis and prompt treatment of any upper respiratory infections are indicated in these patients. In this review, we describe a case of influenza viral pneumonia in an adult liver transplant recipient, review basic and clinical aspects of influenza infection in this patient population, and discuss current modes of prevention and treatment in detail.

Focal hemorrhagic necrosis of the liver. A rare cause of hemoperitoneum.

A 44-year-old white female developed hepatic hemorrhage due to focal hepatic necrosis. This is the only reported case of its kind we have found. No other underlying processes were identified except for the chronic use of oral conjugated estrogens. The possible role of steroids and a possible relationship to the pathogenesis of peliosis hepatis is discussed.

Human leukocyte antigen class I-independent pathways may contribute to hepatitis B virus-induced liver disease after liver transplantation.

The proliferative response of peripheral blood lymphocytes to the HBcAg was compared with serological, molecular and immunohistochemical parameters of hepatitis B virus infection and with biochemical and histological parameters of liver disease in a patient who received a completely human leukocyte antigen class I-mismatched liver allograft for fulminant hepatitis. The proliferative response increased progressively after transplantation, as hepatitis B virus infection became reestablished in the hepatic allograft. Strikingly, the HBcAg-specific T cells suddenly disappeared from the peripheral blood immediately before the acute onset of a severe necroinflammatory liver disease in which more than 80% of the hepatocytes expressed HBcAg. These observations are compatible with the hypothesis that human leukocyte antigen class I-independent hepatitis B virus-specific T cells might play a previously unsuspected role in the pathogenesis of hepatitis B virus-induced liver disease.

Retinal angiomatosis and pancreatic cysts in von Hippel-Lindau disease: use of computed tomography scanning for diagnosis and surveillance.

Reports of the retinal and pancreatic manifestations of von Hippel-Lindau disease have been previously published. We present a case of von Hippel-Lindau disease in which computed tomography scanning was used in a new manner for diagnosis of retinal disease and for diagnosis and surveillance of pancreatic disease. We emphasize the importance of these new findings and recommend the use of yearly CT scanning of the abdomen. This replaces the previous recommendation of exploratory laparotomy in patients with pancreatic lesions. We further advocate that CT surveillance of the offspring of von Hippel-Lindau disease patients begin in the second decade, with the anticipation of curing potentially serious, blinding, or life-threatening lesions.